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Journal of Clinical and Experimental... 2024
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Sulfonamides; Rituximab; Bridged Bicyclo Compounds, Heterocyclic; Retrospective Studies; Male; Aged; Female; Middle Aged; Antineoplastic Combined Chemotherapy Protocols; Japan; Treatment Outcome; Aged, 80 and over; East Asian People
PubMed: 38925975
DOI: 10.3960/jslrt.24014 -
Biological & Pharmaceutical Bulletin 2024We prepared a supramolecular hydrogel composed of decanoic acid and arginine (C10/Arg gel) and evaluated its application to a transdermal formulation. C10/Arg gel...
We prepared a supramolecular hydrogel composed of decanoic acid and arginine (C10/Arg gel) and evaluated its application to a transdermal formulation. C10/Arg gel adjusted to pH 7 with 1 M NaOH aq or 1 M HCl aq provided a translucent hydrogel with a lamellar liquid crystal structure in the concentration region of decanoic acid ≥12% and arginine ≤9%. Rheological measurements showed that C10/Arg gel is a viscoelastic material with both solid and liquid properties, with elasticity being dominant over viscosity in the low shear stress region. The skin permeability of hydrocortisone (HC) and indomethacin (IM) from C10/Arg gels was investigated in vitro using hairless mouse skin and compared to control formulation drug suspensions (IM or HC) in water. The cumulative permeation amount of HC and IM from the C10/Arg gel at 10 h after application was approximately 16 and 11 times higher than that of the control, respectively. On the other hand, the flux of IM decreased with increasing arginine concentration, likely due to the acid-base interaction between Arg and IM in C10/Arg gel. Adequate drug skin permeation enhancement by C10/Arg gel requires optimizing the gel composition for each specific drug.
Topics: Animals; Arginine; Hydrogels; Mice, Hairless; Skin Absorption; Administration, Cutaneous; Skin; Indomethacin; Decanoic Acids; Hydrocortisone; Mice; Rheology; Permeability; Male
PubMed: 38925923
DOI: 10.1248/bpb.b24-00078 -
Anticancer Research Jul 2024Methotrexate (MTX) resistance in osteosarcoma leads to a very poor prognosis. In the present study, in order to further understand the basis and ramifications of MTX...
Reduced Malignancy of Super Methotrexate-resistant Osteosarcoma Cells With Dihydrofolate Reductase Amplification Despite Paradoxical Gain of Oncogenic PI3K/AKT/mTOR and c-MYC expression.
BACKGROUND/AIM
Methotrexate (MTX) resistance in osteosarcoma leads to a very poor prognosis. In the present study, in order to further understand the basis and ramifications of MTX resistance in osteosarcoma, we selected an osteosarcoma cell line that has a 5,500-fold-increased MTX IC Materials and Methods: The super MTX-resistant 143B osteosarcoma cells (143B-MTX) were selected from MTX-sensitive parental human 143B osteosarcoma cells (143B-P) by continuous culture with step-wise increased amounts of MTX. To compare the malignancy of 143B-MTX and 143B-P, colony-formation capacity was compared with clonogenic assays on plastic and in soft agar. In addition, tumor growth was compared with orthotopic xenograft mouse models of osteosarcoma. Expression of dihydrofolate reductase (DHFR), phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), and myelocytomatosis oncogene (MYC) was examined with western immunoblotting and compared in 143B-MTX and 143B-P cells.
RESULTS
143B-MTX had a 5,500-fold increase in the MTX IC compared to the parental 143B-P cells. Expression of DHFR was increased 10-fold in 143B-MTX compared to 143B-P (p<0.01). 143B-MTX cells had reduced colony-formation capacity on plastic (p=0.032) and in soft agar (p<0.01) compared to 143B-P and reduced tumor growth in orthotopic xenograft mouse models (p<0.001). These results demonstrate that 143B-MTX had reduced malignancy. 143B-MTX also showed an increased expression of PI3K (p<0.01), phosphorylated (activated) AKT (p=0.031), phosphorylated mTOR (p=0.043), and c-MYC (p=0.024) compared to 143B-P.
CONCLUSION
The present study demonstrates that the increased expression of DHFR, PI3K/AKT/mTOR and c-MYC appears to be linked to super MTX resistance and, paradoxically, to reduced malignancy. The present results suggest that DHFR may be a powerful tumor suppressor when highly amplified.
Topics: Osteosarcoma; Methotrexate; Humans; Tetrahydrofolate Dehydrogenase; Animals; Drug Resistance, Neoplasm; TOR Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Cell Line, Tumor; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-myc; Mice; Xenograft Model Antitumor Assays; Bone Neoplasms; Gene Amplification; Signal Transduction; Mice, Nude; Antimetabolites, Antineoplastic
PubMed: 38925854
DOI: 10.21873/anticanres.17090 -
BMJ (Clinical Research Ed.) Jun 2024To assess the efficacy and safety of colchicine versus placebo on reducing the risk of subsequent stroke after high risk non-cardioembolic ischaemic stroke or transient... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
To assess the efficacy and safety of colchicine versus placebo on reducing the risk of subsequent stroke after high risk non-cardioembolic ischaemic stroke or transient ischaemic attack within the first three months of symptom onset (CHANCE-3).
DESIGN
Multicentre, double blind, randomised, placebo controlled trial.
SETTING
244 hospitals in China between 11 August 2022 and 13 April 2023.
PARTICIPANTS
8343 patients aged 40 years of age or older with a minor-to-moderate ischaemic stroke or transient ischaemic attack and a high sensitivity C-reactive protein ≥2 mg/L were enrolled.
INTERVENTIONS
Patients were randomly assigned 1:1 within 24 h of symptom onset to receive colchicine (0.5 mg twice daily on days 1-3, followed by 0.5 mg daily thereafter) or placebo for 90 days.
MAIN OUTCOME MEASURES
The primary efficacy outcome was any new stroke within 90 days after randomisation. The primary safety outcome was any serious adverse event during the treatment period. All efficacy and safety analyses were by intention to treat.
RESULTS
4176 patients were assigned to the colchicine group and 4167 were assigned to the placebo group. Stroke occurred within 90 days in 264 patients (6.3%) in the colchicine group and 270 patients (6.5%) in the placebo group (hazard ratio 0.98 (95% confidence interval 0.83 to 1.16); P=0.79). Any serious adverse event was observed in 91 (2.2%) patients in the colchicine group and 88 (2.1%) in the placebo group (P=0.83).
CONCLUSIONS
The study did not provide evidence that low-dose colchicine could reduce the risk of subsequent stroke within 90 days as compared with placebo among patients with acute non-cardioembolic minor-to-moderate ischaemic stroke or transient ischaemic attack and a high sensitivity C-reactive protein ≥2 mg/L.
TRIAL REGISTRATION
ClinicalTrials.gov, NCT05439356.
Topics: Humans; Colchicine; Male; Female; Double-Blind Method; Middle Aged; Ischemic Attack, Transient; Aged; Ischemic Stroke; Treatment Outcome; China; C-Reactive Protein; Adult
PubMed: 38925803
DOI: 10.1136/bmj-2023-079061 -
Journal of the American College of... Jul 2024
Topics: Colchicine; Humans; Familial Mediterranean Fever; Atherosclerosis; Inflammation
PubMed: 38925725
DOI: 10.1016/j.jacc.2024.04.044 -
BMJ Case Reports Jun 2024Scleromalacia perforans, or necrotising anterior scleritis, is a rare and severe form of eye disease that usually occurs in patients suffering from long-standing...
Scleromalacia perforans, or necrotising anterior scleritis, is a rare and severe form of eye disease that usually occurs in patients suffering from long-standing systemic inflammatory diseases, with rheumatoid arthritis (RA) being the most common. Here, we report the case of a patient who presented with redness of the eye and discolouration of the sclera and was diagnosed with scleromalacia perforans without any further extraophthalmic systemic involvement. Serological workup revealed highly positive cyclic citrullinated peptide (CCP) antibody (CCP-IgG/anticitrullinated protein antibodies) and positive rheumatoid factor, serologies commonly associated with RA. The patient's symptoms responded very well to rituximab therapy.
Topics: Humans; Arthritis, Rheumatoid; Scleritis; Rituximab; Female; Rheumatoid Factor; Antirheumatic Agents; Middle Aged; Peptides, Cyclic; Male
PubMed: 38925670
DOI: 10.1136/bcr-2024-259863 -
International Journal of Rheumatic... Jun 2024Mixed connective tissue disease (MCTD) is a rare entity in children. There is a paucity of studies on juvenile-onset MCTD (jMCTD) worldwide especially from Southeast...
INTRODUCTION
Mixed connective tissue disease (MCTD) is a rare entity in children. There is a paucity of studies on juvenile-onset MCTD (jMCTD) worldwide especially from Southeast Asia.
OBJECTIVES
To describe clinical and laboratory features of jMCTD diagnosed at pediatric rheumatology centers across India.
METHODS
A predesigned detailed case proforma in an excel format was prepared and was sent to all the Pediatric Rheumatology centers in India. Eleven centers provided the clinical and laboratory data of their jMCTD patients, which was then compiled and analyzed in detail.
RESULTS
Thirty-one jMCTD patients from 11 centers were included in the study. Our cohort had 27 females and four male patients over 12 months (August 2021 to July 2022). The median age at presentation was 12 years (range 5-18 years) and the median duration of symptoms was 24 months at diagnosis (range 2-96 months). The common features included arthritis (90%), malar rash (70.9%), and Raynaud's phenomenon (70.9%). At a mean follow-up of 43 months (range 1-168 months), 45% of them were in remission. There were two deaths reported, due to macrophage activation syndrome and sepsis respectively.
CONCLUSION
We present the largest multicenter experience on jMCTD from the Indian subcontinent. The study's findings serve as a crucial stepping stone toward unraveling the complexities of jMCTD and improving patient care and management strategies.
Topics: Humans; Child; Male; Female; Mixed Connective Tissue Disease; India; Adolescent; Child, Preschool; Treatment Outcome; Age of Onset; Immunosuppressive Agents; Antirheumatic Agents; Retrospective Studies; Time Factors; Remission Induction
PubMed: 38925615
DOI: 10.1111/1756-185X.15243 -
The New England Journal of Medicine Jun 2024Dupilumab is a human monoclonal antibody that blocks interleukin-4 and interleukin-13 pathways and has shown efficacy in five different atopic diseases marked by type 2... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Dupilumab is a human monoclonal antibody that blocks interleukin-4 and interleukin-13 pathways and has shown efficacy in five different atopic diseases marked by type 2 inflammation, including eosinophilic esophagitis in adults and adolescents.
METHODS
In this phase 3 trial, we randomly assigned, in a 2:2:1:1 ratio, patients 1 to 11 years of age with active eosinophilic esophagitis who had had no response to proton-pump inhibitors to 16 weeks of a higher-exposure or lower-exposure subcutaneous dupilumab regimen or to placebo (two groups) (Part A). At the end of Part A, eligible patients in each dupilumab group continued the same regimen and those in the placebo groups were assigned to higher-exposure or lower-exposure dupilumab for 36 weeks (Part B). At each level of exposure, dupilumab was administered in one of four doses tiered according to baseline body weight. The primary end point was histologic remission (peak esophageal intraepithelial eosinophil count, ≤6 per high-power field) at week 16. Key secondary end points were tested hierarchically.
RESULTS
In Part A, histologic remission occurred in 25 of the 37 patients (68%) in the higher-exposure group, in 18 of the 31 patients (58%) in the lower-exposure group, and in 1 of the 34 patients (3%) in the placebo group (difference between the higher-exposure regimen and placebo, 65 percentage points [95% confidence interval {CI}, 48 to 81; P<0.001]; difference between the lower-exposure regimen and placebo, 55 percentage points [95% CI, 37 to 73; P<0.001]). The higher-exposure dupilumab regimen led to significant improvements in histologic, endoscopic, and transcriptomic measures as compared with placebo. The improvements in histologic, endoscopic, and transcriptomic measures between baseline and week 52 in all the patients were generally similar to the improvements between baseline and week 16 in the patients who received dupilumab in Part A. In Part A, the incidence of coronavirus disease 2019, nausea, injection-site pain, and headache was at least 10 percentage points higher among the patients who received dupilumab (at either dose) than among those who received placebo. Serious adverse events were reported in 3 patients who received dupilumab during Part A and in 6 patients overall during Part B.
CONCLUSIONS
Dupilumab resulted in histologic remission in a significantly higher percentage of children with eosinophilic esophagitis than placebo. The higher-exposure dupilumab regimen also led to improvements in measures of key secondary end points as compared with placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; EoE KIDS ClinicalTrials.gov number, NCT04394351.).
Topics: Humans; Eosinophilic Esophagitis; Antibodies, Monoclonal, Humanized; Male; Female; Child; Double-Blind Method; Child, Preschool; Infant; Eosinophils; Injections, Subcutaneous; Dose-Response Relationship, Drug; Esophagus; Interleukin-13; Remission Induction; Interleukin-4
PubMed: 38924731
DOI: 10.1056/NEJMoa2312282 -
International Journal of Rheumatic... Jun 2024To compare antibody responses after vaccinations between patients with rheumatoid arthritis (RA) and patients with metabolic disorders (MD). The study places special... (Observational Study)
Observational Study Comparative Study
Diminished antibody response to SARS-CoV-2 in rheumatoid arthritis compared to metabolic disorders following the primary series of vaccinations and its recovery with a booster: A single-center prospective observational study.
AIM
To compare antibody responses after vaccinations between patients with rheumatoid arthritis (RA) and patients with metabolic disorders (MD). The study places special emphasis on understanding how common diseases affect antibody responses in individuals with RA within real-world settings.
METHODS
The participants were 117 patients with RA (66 with RA only and 51 with RA and MD) and 37 patients with MD who received both the primary series of vaccinations and a booster. Antibody titers were compared after the primary series of vaccinations and a booster, and factors influencing the antibody response were assessed.
RESULTS
Following the primary series of vaccinations, a significant reduction in antibody titers was observed in patients with longer days between vaccination and antibody measurement, the use of IL-6 inhibitors, selective T cell co-stimulation modulators, and methotrexate. Comorbid MD did not exhibit significant influences on antibody response in RA. Notably, the presence of RA itself was not significant in multivariate linear regression analysis. After the administration of the booster, however, day between vaccination and antibody measurement, the use of IL-6 inhibitor, and methotrexate no longer remained significant. Only the use of selective T cell co-stimulation modulators retained its significance.
CONCLUSIONS
MD did not exhibit a significant impact on antibody responses in RA patients. The reduced antibody response following the primary series in RA patients appeared to be attributed more to specific RA medications rather than to the disease itself. Booster vaccines are vital in restoring the antibody response in RA.
Topics: Humans; Arthritis, Rheumatoid; Male; Female; Middle Aged; Prospective Studies; COVID-19; Aged; Antibodies, Viral; SARS-CoV-2; Metabolic Diseases; COVID-19 Vaccines; Antibody Formation; Immunization, Secondary; Adult; Vaccination; Antirheumatic Agents
PubMed: 38924257
DOI: 10.1111/1756-185X.15203 -
Proceedings of the National Academy of... Jul 2024Immune checkpoint therapies (ICT) improve overall survival of patients with cancer but may cause immune-related adverse events (irAEs) such as myocarditis. Cytotoxic T...
Immune checkpoint therapies (ICT) improve overall survival of patients with cancer but may cause immune-related adverse events (irAEs) such as myocarditis. Cytotoxic T lymphocyte-associated antigen 4 immunoglobulin fusion protein (CTLA-4 Ig), an inhibitor of T cell costimulation through CD28, reverses irAEs in animal models. However, concerns exist about potentially compromising antitumor response of ICT. In mouse tumor models, we administered CTLA-4 Ig 1) concomitantly with ICT or 2) after ICT completion. Concomitant treatment reduced antitumor efficacy, while post-ICT administration improved efficacy without affecting frequency and function of CD8 T cells. The improved response was independent of the ICT used, whether CTLA-4 or PD-1 blockade. The frequency of Tregs was significantly decreased with CTLA-4 Ig. The resulting increased CD8/Treg ratio potentially underlies the enhanced efficacy of ICT followed by CTLA-4 Ig. This paradoxical mechanism shows that a CTLA-4 Ig regimen shown to reduce irAE severity does not compromise antitumor efficacy.
Topics: Animals; Mice; Immunotherapy; CTLA-4 Antigen; Immune Checkpoint Inhibitors; CD8-Positive T-Lymphocytes; T-Lymphocytes, Regulatory; Cell Line, Tumor; Abatacept; Female; Humans; Mice, Inbred C57BL; Neoplasms; Programmed Cell Death 1 Receptor
PubMed: 38923991
DOI: 10.1073/pnas.2404661121